As life expectancy increases Alzheimer's disease (AD) is becoming a major health problem in the western world. There has been intensive research aimed at identifying a reliable cure or preventive measures for the disease, so far withput success.
One of the biggest problems in the design and testing of any therapeutic agent is the lack of reliable clinical diagnostic criteria that could identify AD sufferers early enough for any meaningful intervention. However, the currently available clinical diagnostic tools do not allow an accurate and reliable diagnosis of Alzheimer's disease in other than severely demented patients. Furthermore they do not allow the identification of subjects with pre-clinical Alzheimer's disease who could benefit from preventive intervention.
The most often used clinical diagnostic criteria are the NINCDS/ADRDA criteria (McKhann, G. et al., (1984) Neurology 34: 939-944), originally designed for research purposes. These criteria are highly sensitive but have a low specificity. This is due to the fact that the positive predictive value of a diagnosis of “probable” or “possible” Alzheimer's disease is very high, but the negative predictive value is very low (13). In other terms, if a patient fulfils the requirements of the NINCDS/ADRDA criteria for Alzheimer's disease it is highly likely that the patient indeed has got Alzheimer's disease. However, a proportion of the patients who do not fulfill these criteria (e.g. are regarded as controls) are found to have Alzheimer's disease at post mortem examination (13).
As a consequence of their low specificity, the NINCDS/ADRDA criteria are not ideal for clinical diagnostic purposes. Additionally they are not suitable as diagnostic criteria for clinical trials looking at preventive or curative therapies that may have their best chance of being effective if used before significant dementia has developed. Thus there remains a need for a reliable diagnostic test for Alzheimer's disease, and in particular for a test which may be used in the early detection of subjects with pre-clinical Alzheimer's disease who could benefit from preventive intervention.
In recent years it is becoming more widely accepted that the pathogenic basis of Alzheimer's disease is the aberrant re-entry of different neuronal populations into the cell division cycle (14). In healthy elderly individuals rapid cell cycle arrest and re-differentiation may follow this cell cycle re-entry. In contrast, in individuals with Alzheimer's disease the regulatory mechanisms appear to fail and the neurons progress into the late stages of the cell cycle leading to the accumulation of AD-related pathology and/or neuronal death (14).
Studies by the present inventor and others indicate that the cell cycle regulatory failure in Alzheimer's disease occurs at the G1/S transition checkpoint (3). Previous studies on fibroblasts and lymphocytes from Alzheimer's disease patients indicate that the regulation of the cell division cycle might be disrupted in cells other than neurons in this condition (8, 9, 17). It is also known that Alzheimer's disease patients are more prone to some forms of cancer (4) and that Down's syndrome patients, who develop AD in early adult life, are more prone to leukaemia than the general population (7, 10). It is plausible therefore to hypothesis that the cell cycle regulatory failure in neurons, even in early (pre-clinical) stages of AD, might be reflected by similar cell cycle regulatory malfunction in lymphocytes.
The present inventor has now shown that the in vitro responsiveness of lymphocytes to G1 inhibitor treatment is significantly less effective in Alzheimer's disease patients than in control subjects. Additionally, in subjects showing clinical signs of incipient Alzheimer's disease the lymphocyte-response is similar to that seen in Alzheimer's disease patients. These findings represent direct evidence to support the hypothesis that the failure of the G1/S transition control is not restricted to neurons in Alzheimer's disease patients, but also occurs in peripheral cells, such as lymphocytes.
The observation that the regulatory defect at the G1/S transition also occurs in peripheral cells provides the basis for new clinical tests, useful in the diagnosis of Alzheimer's disease, that rely on eliciting the activation of the G1/S transition checkpoint in non-neuronal cells, such as lymphocyte cultures. Since cell cycle regulatory failure in neurons appears to be a very early event in the pathogenesis of Alzheimer's disease, it is anticipated that such tests will be of use for the identification of subjects in the pre-clinical stages of Alzheimer's disease who do not fulfill the requirements of the NINCDS/ADRDA criteria for dementia, but would benefit from early intervention with preventive measures for Alzheimer's disease.